Strategies to address recruitment to a randomised trial of surgical and non-surgical treatment for cancer: results from a complex recruitment intervention within the Mesothelioma and Radical Surgery 2 (MARS 2) study

Objectives Recruiting to randomised trials is often challenging particularly when the intervention arms are markedly different. The Mesothelioma and Radical Surgery 2 randomised controlled trial (RCT) compared standard chemotherapy with or without (extended) pleurectomy decortication surgery for malignant pleural mesothelioma. Anticipating recruitment difficulties, a QuinteT Recruitment Intervention was embedded in the main trial phase to unearth and address barriers. The trial achieved recruitment to target with a 4-month COVID-19 pandemic-related extension. This paper presents the key recruitment challenges, and the strategies delivered to optimise recruitment and informed consent. Design A multifaceted, flexible, mixed-method approach to investigate recruitment obstacles drawing on data from staff/patient interviews, audio recorded study recruitment consultations and screening logs. Key findings were translated into strategies targeting identified issues. Data collection, analysis, feedback and strategy implementation continued cyclically throughout the recruitment period. Setting Secondary thoracic cancer care. Results Respiratory physicians, oncologists, surgeons and nursing specialists supported the trial, but recruitment challenges were evident. The study had to fit within a framework of a thoracic cancer service considered overstretched where patients encountered multiple healthcare professionals and treatment views, all of which challenged recruitment. Clinician treatment biases, shaped in part by the wider clinical and research context alongside experience, adversely impacted several aspects of the recruitment process by restricting referrals for study consideration, impacting eligibility decisions, affecting the neutrality in which the study and treatment was presented and shaping patient treatment expectations and preferences. Individual and group recruiter feedback and training raised awareness of key equipoise issues, offered support and shared good practice to safeguard informed consent and optimise recruitment. Conclusions With bespoke support to overcome identified issues, recruitment to a challenging RCT of surgery versus no surgery in a thoracic cancer setting with a complex recruitment pathway and multiple health professional involvement is possible. Trial registration number ISRCTN ISRCTN44351742, Clinical Trials.gov NCT02040272.


Introducing MARS 2
• Approach all potentially eligible patients so that everyone has an opportunity to consider participation (including those with biphasic and sarcomatoid disease).
• Mention the study early on and explain the equipoise ('Because we don't know if chemotherapy on its own or chemotherapy with surgery is best we're taking part in a study called MARS 2').Be mindful to convey equipoise throughout.• Request patients to 'keep an open mind' until all information is heard.

Discussing the study
• Present MARS 2 in an enthusiastic and straight-forward manner.
• It is better to use the term 'study' rather than 'trial' as trial means different things to different patients and can therefore be confusing (e.g.'trial and error', 'experimental', 'guinea pig').
• It can be good to mention that MARS 2 is a study funded by the NIHRthe NHS funding bodyand is being carried out in over 25 centres around the UK.
• Describe the benefits of study participation, e.g.close follow-up and monitoring, and that the aim of research is to produce evidence so that future patients will not have to face current treatment uncertainties.
• Be clear that participation is voluntary and that their care will not be affected in anyway if they choose not to participate."Neither of the treatments in the study are experimental, they have been used for years.

Balancing the treatments
The surgeon and oncologist have deemed them suitable for you."• Continue with the conversation until you feel they are sufficiently open minded to consider either treatment option, in which case they are in an ideal position to be recruited.If they still have a clear preference, and you are satisfied that they are well-informed following the discussion, then they should not be recruited.This will minimise the risk of crossover.
• Patients preferences often dissipate following gentle exploration and balanced information.

Describing randomisation
• Randomisation is a familiar concept but it can be difficult to explain in a way that makes sense to patients in the context of a trial.
• Randomisation may not make sense to patients if they do not grasp why it is being done, so it is important to explain both the purpose and process of randomisation, e.g.
"We don't know if it's better to have chemotherapy alone or with surgery so we want a fair comparison of the treatment options (purpose).We use a process of randomisation to produce two groups of patients that are similar except for the treatment received (process).This will enable us to do a fair comparison.You will have an equal chance of receiving chemotherapy alone or chemotherapy with surgery.If you or I chose then the groups are unlikely to be the same and the results may not be reliable."• It is helpful to avoid using terms such as 'toss of a coin' or 'decided by a computer'.Metaphors have been viewed as being quite flippant for something so serious, and reference to a computer deciding has led to confusion that the computer is choosing the 'best' option for them.
• Randomisation can actually be a solution to uncertainty if the patient is unsure what to do.
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)

• You are not expected to give detailed information about chemotherapy or surgery if you do not specialise in it, but you can still ensure that you convey equipoise throughout the consultation when explaining treatments: o Remind patients that we do not know if chemotherapy on its own or in combination with
surgery is best, hence the need for the study.o When outlining the treatments think 'balance'are you inadvertently steering patients?Patients often ask clinicians what they think is best.Refrain from providing your own personal beliefs to avoid confusing or influencing patients and emphasise equipoise e.g.
o Avoid loaded terminology (i.e.'gold standard', 'experimental') o Balance the potential advantages and disadvantages of the treatments e.g."Those are the risks of surgery, but then as I said it comes back to that balance of risks and benefitswhat are the potential benefits of surgery with chemotherapy….How then does this compare with the chemotherapy alone…" • "I think that is a really difficult question because we don't genuinely know which is the best option.We just don't have enough information to say which treatment will be best for which patient, which is why we're doing this study.Both treatments have their pros and cons and have been assessed as being suitable for you.I would be happy to recommend the study to my close friends and family."BMJPublishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)

ask any questions -thank you for your continued support! Exploring patient preferences •
It can be common for patients to arrive at a consultation with an expectation/preference about what treatment they would like.It is still important to discuss the study fully so that patients can make an informed decision about treatment options and study participation.•

Strategies for responding to preferences: o
Acknowledge their preference and open up the conversation -"Ok, but…" is a good way to ensure this, e.g."Ok it's great that you've read up on the surgery, but let's just consider what surgery means" o Remind patients to keep an 'open mind' until they've heard all information, e.g."But what I'd like you to do is just keep an open mind whilst I run through the treatments.Emphasise the position of uncertainty and not knowing which treatment option is best, e.g.
o Balance their views, tailored to any concerns they may have, e.g."Ok I accept what you say that surgery with chemotherapy is appealing because the cancer is removed, but we don't know if it makes any difference to your survival and the operation has associated risks.Chemotherapy alone is the current standard of care provided in both arms and does not have the associated risks of surgery."o "What you've got to remember is that both are good options that are suitable for you.If we knew which one was better we would recommend it."o Reassure patients about both treatments, e.g.